Autologous stem cell transplantation in multiple myeloma: outcome in patients with renal failure

The impact of renal failure on prognosis of multiple myeloma patients treated with high-dose chemotherapy and stem cell support is incompletely studied. A total of 137 patients received high-dose chemotherapy with autologous transplantation at our centre. The patient population was divided into three groups based on their estimated creatinine clearance (Ccr); renal failure defined as Ccr < 60 mL/min: Group A: normal renal function both at diagnosis and at transplant (n = 78), Group B: renal failure at diagnosis but normal renal function at transplant (n = 30), Group C: renal failure both at diagnosis and at transplant (n = 29). There were no differences in the number of stem cells harvested, time to engraftment or response to transplantation between the groups. Ten of the patients in Group C had a normalisation of renal function post-transplant. Significantly longer hospitalisation, increased use of blood products and increased number of infections were seen in Group C compared to Groups A and B. The transplant-related mortality was 17% in Group C compared to 0% and 1% in Groups B and A respectively. Eight patients were on dialysis during transplant and four of these died within the first 100 d post-transplant. Disease response was similar in the three groups. Overall survival was significantly longer in Group A than in Groups B and C. High-dose chemotherapy with autologous transplantation is feasible in MM with renal failure. Whereas patients with moderate renal insufficiency seem to benefit from this treatment, patients in need for dialysis at the time of transplant must be carefully evaluated before proceeding to high-dose chemotherapy.     

Results of autologous stem cell transplant in multiple myeloma patients with renal failure

Data are presented on 81 multiple myeloma (MM) patients with renal failure (creatinine > 176.8 micromol/l) at the time of autologous stem cell transplantation (auto-SCT), including 38 patients on dialysis. The median age was 53 years (range: 29-69) and 26% had received more than 12 months of prior chemotherapy. CD34+ cells were mobilized with granulocyte colony-stimulating factor (G-CSF) alone (n = 51) or chemotherapy plus G-CSF (n = 27), yielding medians of 10 and 16 x 106 CD34+ cells/kg respectively (P = 0.003). Sixty patients (27 on dialysis) received melphalan 200 mg/m2 (MEL-200). Because of excessive toxicity, the subsequent 21 patients (11 on dialysis) received MEL 140 mg/m2 (MEL-140). Thirty-one patients (38%) completed tandem auto-SCT, including 11 on dialysis. Treatment-related mortality (TRM) was 6% and 13% after the first and second auto-SCT. Median times to absolute neutrophil count (ANC) > 0.5 x 109/l and to platelets > 50 x 109/l were 11 and 41 d respectively. Non-haematological toxicities included mucositis, pneumonitis, dysrhythmias and encephalopathy. At a median follow up of 31 months, 30 patients have died. Complete remission (CR) was achieved in 21 patients (26%) after first SCT and 31 patients (38%) after tandem SCT. Two patients discontinued dialysis after SCT. Median durations of complete remission (CR) and overall survival (OS) have not been reached; probabilities of event-free survival (EFS) and OS at 3 years were 48% and 55% respectively. Dialysis dependence and MEL dose did not affect EFS or OS. Sensitive disease prior to SCT, normal albumin level and younger age were independent prognostic factors for better OS. In conclusion, renal failure had no impact on the quality of stem cell collections and did not affect engraftment. MEL-140 had an acceptable toxicity and appeared equally effective as MEL-200. In the setting of renal failure, the role of auto-SCT early in the disease course and benefits of tandem SCT require further evaluation.     

A rare case of interstitial pneumonitis after tandem high-dose melphalan conditioning and autologous stem cell transplantation in multiple myeloma

A 57-yr-old woman with multiple myeloma received an autologous tandem transplant at a 4-month interval. She was conditioned twice with 225 mg/m2 melphalan. After the second transplant, interstitial pneumonitis (IP) ensued. The clinical course was life threatening and mechanical ventilation was required for 32 d. All attempts to identify an infectious agent failed. A presumptive diagnosis of idiopathic IP, possibly related to melphalan toxicity, was made. High-dose methylprednisolone administration led to rapid and durable improvement. Melphalan was employed for conditioning in the tandem setting with an interval of only 3-4 months between two courses or a dose elevation to 225 instead of 200 mg/m2, may have induced IP which responded favorably to methylprednisolone.     

Busulfan and melphalan as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma

Summary. Twenty-four patients with multiple myeloma (MM), three (12-5%) in complete remission (CR) and 21 (87-5%) in partial remission (PR) were treated with high-dose chemotherapy (HDCT) (busulfan 12 mg/kg-l-melphalan 140mg/m²) as preparative regimen for autologous peripheral blood stem cell (PBSC) transplantation. These cells were previously collected by leukapheresis after mobilization by high-dose cyclophosphamide (HD Cy) + rhGM-CSF (18 patients) or rhG-CSF alone (six patients). Considering 23 evaluable patients following HDCT, the CR rate was 58% (14 patients) and the PR rate was 38% (nine patients). One transplant-related death occurred following this regimen (4%). With a median follow-up of 20 months (range 4-34) after transplantation, 21 patients are alive (87%). Disease progression after transplantation was observed in four patients. Overall and relapse-free actuarial survival at 24 months was 91% and 74%, respectively. 12 patients (50%) remain in CR 15 months (4-34) post transplant. The major toxicity was mucositis. Busulfan + melphalan is a safe and feasible conditioning regimen for APBSCT in MM with acceptable toxicity and a high objective response rate, which may result in prolonged survival.     

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single‐dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end‐stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre‐ and post‐dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.     

Cardiac toxicity of high-dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation

Tandem autologous hematopoetic stem cell transplantation (HSCT) is an effective treatment in patients with multiple myeloma (MM). Patients receive high-dose cyclophosphamide (CY) followed by two myeloablative dosages of melphalan (MEL). Cardiotoxicity treatment related data are scanty. In 30 patients with MM chemotherapy was followed by high-dose CY (cycle CY), and two autologous tandem HSCT treatments with MEL (cycles MEL I and MEL II). During each 15-day treatment troponin I (TnI), brain natriuretic peptide (BNP) and endothelin-1 (ET-1) were controlled at six time points. All patients underwent conventional and tissue Doppler echocardiography prior to CY therapy (Eho 0), before cycle MEL I (Eho 1), before cycle MEL II (Eho 2), and 3 months after the completion of therapy (Eho 3). None of the patients developed clinical signs of heart failure. The peak TnI concentrations were noted at days 8, 11, and 15 during all three chemotherapy cycles. During all three cycles there was a significant increase in baseline BNP concentrations and BNP levels measured at day 1 after treatment with CY and MEL (CY: P = 0.0001, MEL I: P = 0.001, MEL II: P = 0.001). The highest BNP concentration occurred during CY treatment (0.517 +/- 0.391 mug/L). During cycles MEL I and MEL II we noted the peak BNP concentrations at day 4 following chemotherapy (MEL I 0.376 +/- 0.418 mug/L; MEL II 0.363 +/- 0.379 mug/L). During all three cycles the highest ET-1 levels occurred at day 1 after chemotherapy (CY 1.146 +/- 1.313 ng/L; MEL I 1.054 +/- 2.242 ng/L; MEL II 0.618 +/- 0.539 ng/L). A significant increase in ET-1 concentrations relative to the basal values occurred only in cycle MEL II (P = 0.003). The duration of wave a in the Doppler pulmonary vein flow increased significantly (Eho 0/Eho 1: P = 0.008, Eho 0/Eho 3: P = 0.026). There was a significant decrease in the A/a ratio in flow velocities during chemotherapy (Eho 0/Eho 1: P = 0.002, Eho 0/Eho 3: P < 0.0001). Early diastolic tissue Doppler velocities (E (m)) decreased significantly during individual cycles of chemotherapy (P = 0.006). A significant post-treatment increase in the incidence of mitral regurgitation was observed (Eho 0/Eho 3: P = 0.003). Treatment of MM patients with tandem autologous HSCT is cardiotoxic. Our patients did not develop clinically overt heart failure or myocardial necrosis. Increased plasma levels of BNP and ET-1 were compatible with transient neurohormonal activation of heart failure. Doppler echocardiography studies revealed worsening of left ventricular diastolic function and occurrence of functional mitral regurgitation.     

Myeloma cell contamination of peripheral blood stem-cell grafts can predict the outcome in multiple myeloma patients after high-dose chemotherapy and autologous stem-cell transplantation

Purpose High-dose chemotherapy with hematopoietic stem-cell rescue is increasingly being used in the treatment of multiple myeloma. Bone marrow and also peripheral blood stem-cell (PBSC) grafts contain measurable quantities of plasma cells, the biological significance of which is unknown.Methods Patients with multiple myeloma were mobilized with chemotherapy and filgrastim. The number of CD38++/CD138+ cells/kg in the grafts for autologous transplantation was determined by flow cytometry. Patients were stratified into two groups (threshold 4.5×10⁵ plasma cells kg^-1) of reinfused plasma cells in the first autologous graft.Results The median statistical progression-free survival was 14 months (4–34 months) in the high-contamination group (>4.5×10⁵ plasma cells kg^-1) compared to 26 months (4–43 months) in the low-contamination group (<4.5×10⁵ plasma cells kg^-1, P =0.0096). Patients with 13q deletion were more frequently found to have a high contamination of the stem-cell graft with malignant plasma cells.Conclusions Patients with graft contamination of more than 4.5×10⁵ plasma cells kg^-1 had a high risk of early disease progression after high-dose chemotherapy. In vivo tumor cell purging prior to mobilization chemotherapy might be one strategy to improve the time to progression of high-risk patients.     

A pilot study of 220 mg/m2 melphalan followed by autologous stem cell transplantation in patients with advanced haematological malignancies: pharmacokinetics and toxicity

We studied the pharmacokinetics and toxicity of 220 mg/m² melphalan (HDM 220) followed by autologous stem cell transplantation in 16 patients with advanced haematological malignancies. Pharmacokinetic parameters (mean values of steady-state volume of distribution 14.6 l/m², total body clearance 313 ml/min/m², elimination half-life 46 min) were the same as those of 140 or 200 mg/m² melphalan in previous reports. HDM 220 was feasible. Extramedullary toxicity was mainly W.H.O. grade 4 mucositis (13/16 patients). The median duration of 41 d (10, not reached) of thrombocytopenia <25 × 10⁹/l was long. In multiple myeloma the response rate was 89% in heavily pretreated patients, suggesting that HDM 220 could be considered earlier in the course of the disease as an alternative consolidation therapy.     

Long-term follow up of patients with multiple myeloma after high-dose chemotherapy and allogeneic stem cell transplantation

OBJECTIVES: Allogeneic transplantation may offer a curative approach to multiple myeloma (MM). We retrospectively analyzed the outcome of patients with multiple myeloma undergoing allogeneic stem cell transplantation in the context of beta(2) microglobulin and chromosome 13q. METHODS: All 13 patients with MM, who were referred to our center for allogeneic stem cell transplantation, were evaluated. Median age of patients was 38 yr, eight patients had chemo-sensitive disease, and median time between diagnosis of MM and transplantation was 15 months. Engraftment, acute and chronic graft vs. host disease, response to treatment, disease-free survival, and overall survival were evaluated according to standard criteria. RESULTS: There was one transplant-related death. Among 12 evaluable patients, seven patients (58%) achieved a complete remission (CR), and four patients (33%) achieved a partial remission. Acute graft vs. host disease occurred in 46% of patients, and chronic graft vs. host disease in 42% of available patients. After a median follow-up of 69.5 months (range, 5-128) nine patients (70%) are still alive, and six of them have remained progression free. Among five patients with low beta(2) microglobulin and normal chromosome 13q, four patients achieved a CR, with CR duration >5 yr in three of them. Among seven patients with elevated ss(2) microglobulin and/or deletion of chromosome 13q, only three CR were observed, with two patients still in CR on days +920 and +161, respectively. CONCLUSIONS: Allogeneic stem cell transplantation in patients with MM results in promising rates of CR, but durable remissions are predominantly seen in patients with favorable prognostic parameters.     

High-dose chemotherapy and autologous peripheral blood stem cell transplantation in high-risk multiple myeloma

We compared the effect of high-dose therapy together with autologous peripheral blood stem cell transplantation (autoPBSCT) in 60 patients with multiple myeloma (MM) with 90 patients who underwent conventional chemotherapy. We scored the prognostic factors according to our reported classification system that includes measurements of serum albumin, serum beta-2-microglobulin, and morphology of myeloma cells selected by multivariate analysis. We separated the patients into three risk groups at stratification level I (low, intermediate and high) and into two risk groups at stratification level II (low and high). AutoPBSCT tended to be as effective for high, as for low-risk patients in level I, and was obviously as helpful for high, as for low-risk patients in stratification II. In conclusion, high-risk patients with MM should be treated with high-dose therapy accompanied with autoPBSCT like low-risk patients.     

An overview of high-dose melphalan and stem cell transplantation in the treatment of AL amyloidosis

AL amyloidosis is the most common form of systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. This review outlines an overview of high-dose intravenous melphalan and stem cell transplantation in the treatment of AL amyloidosis. An algorithm of our recommendations for the treatment of AL amyloidosis is also outlined.     

High-dose melphalan with autologous stem cell transplantation after VAD induction chemotherapy for treatment of amyloid light chain amyloidosis: a single centre prospective phase II study

Amyloid light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which monoclonal light chains transform to amyloid deposit in various tissues and can lead to organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10-14 months. With high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), haematological and clinical remission rates of up to 50% of treated patients have been reported from phase II studies. HDM followed by ASCT appears to prolong survival in patients, if haematological remission can be reached. In this phase II study, we evaluated vincristine, adriamycin and dexamethasone (VAD) as induction chemotherapy prior to stem cell mobilization and HDM with ASCT. The regimen was, in general, feasible in patients with AL amyloidosis, but VAD chemotherapy had a considerable World Health Organization (WHO) grade III-IV toxicity (25%) and mortality (7%) rate. VAD pretreatment did not interfere with stem cell mobilization and HDM with ASCT was possible in 86% of patients. The overall treatment efficacy was comparable with reported results of HDM and ASCT without preceding chemotherapy. We could not show an additional benefit of VAD induction in terms of increasing haematological response rate; however the 13% mortality rate after HDM and ASCT in our series was lower than the previous report.     

多发性骨髓瘤患者自体造血干细胞移植后感染的临床特征

目的 了解多发性骨髓瘤(MM)自体造血干细胞移植(ASCT)后感染的临床特点.方法 回顾性分析在中山大学附属第一医院住院诊治并接受ASCT治疗的37例MM患者,记录移植后6个月内的感染类型、时间、病原体以及疗效和转归.结果 在ASCT后6个月内有33例(89.2%)患者在观察期间出现59例次感染,其中30例患者在观察期间出现34例次(57.6%)细菌感染,12例患者在观察期间出现15例次(25.4%)真菌感染.既往曾合并真菌感染患者在移植后发生真菌感染比例高于没有合并真菌感染的患者(P=0.040).观察期间分别出现4例(6.8%)巨细胞病毒(CMV)、3例(5.1%)带状疱疹病毒感染及3例(5.1%)HBV再激活.移植后早期感染中细菌感染占62.8%,真菌感染28.6%,病毒感染8.6%,其中病毒感染均为CMV感染,移植后早期未见水痘带状疱疹病毒和HBV感染.移植后中期感染中细菌感染占50.0%、真菌感染20.8%、病毒感染29.3%,移植后早期与中期感染比例差异无统计学意义(P=0.106).38例次(64.4%)感染在应用首选抗感染治疗即得到控制.3例(8.1%)由于感染相关死亡.结论 MM患者ASCT后感染发生率高,各种病原体均易感,需要尽早合理抗感染治疗,降低感染相关病死率.

Abstract：

Objective To explore the clinical features of infection in multiple myeloma (MM)undergoing autologous hematopoietic stem cell transplantation (ASCT). Methods Thirty-seven patients with MM undergoing ASCT were retrospectively analyzed for type and time of infection, pathogen, and outcome. Results Fifty-nine cases of infectious complications occurred in 33 patients (89. 2% ) after ASCT, with 34 cases (57.6%) of bacterial infections in 30 patients, 15 cases (25.4%) of fungal infections in 12 patients, 4 cases (6. 8% ) of cytomegalovirus (CMV) infection, 3 cases (5. 1% ) of herpes zoster virus infection and 3 cases (5. 1% ) of HBV reactivation. The proportion of bacterial infection, fungal infection and virus infection were 62. 8%, 28.6% and 8. 6% respectively in the early stage after ASCT, and 50. 0%, 20. 8% and 29. 3% respectively in the median stage. Response to first-line antibiotic therapy was seen in 38 cases (64. 4% ). Infection-related mortality was 8. 1% (3 cases). Conclusions The incidence of infection in MM patients undergoing ASCT is high and they are susceptible to all pathogens. It is important to choose the right antifungal agents as quickly as possible to reduce infection-related mortality.     

Effect of high-dose melphalan and peripheral blood stem cell transplantation on renal function in patients with multiple myeloma and renal insufficiency: a case report and review of the literature

 Multiple myeloma with IgG-lambda monoclonal gammopathy and severe renal impairment with light-chain deposit disease was diagnosed in a 51-year-old man. Following conventional therapy with VAD (vincristine, adriamycin, dexamethasone) a partial remission was achieved. Peripheral blood stem cells (PBSC) were then collected following mobilization with cyclophosphamide and recombinant human granulocyte colony-stimulating factor and enriched for CD34-positive cells by immunoaffinity column. Fourteen months after diagnosis high-dose melphalan was given, followed by infusion of CD34-positive PBSC. Aside from mild oral mucositis and trigonitis, high-dose therapy was tolerated well. After he underwent PBSC transplantation his renal function improved, and the patient has been in in continuous complete remission for 1 year. Thus, high-dose chemotherapy can be safely administered to patients with multiple myeloma and severe renal impairment. Our findings confirm previous reports summarized in the current presentation. Received: August 3, 1998 / Accepted: November 2, 1998     

IgM AL amyloidosis due to B cell lymphoproliferative disorder: efficacy of high-dose melphalan followed by autologous stem cell transplantation

This report concerns a patient with IgM AL amyloidosis due to a B cell lymphoproliferative disorder who was successfully treated with VAD and subsequent high-dose melphalan followed by autologous stem cell support. After this chemotherapeutic regimen, the patient showed complete hematological remission and improvement in nephrotic syndrome. These findings suggest that high-dose melphalan may also be effective for lymphoplasmacytoid cells producing monoclonal IgM which are phenotypically distinct from plasma cells. Myeloablative therapies, such as high-dose melphalan, should definitely be considered as a treatment option for AL amyloidosis, irrespective of the type of precursor immunoglobulin.     

Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure

Salvage therapy of patients with advanced, relapsed and refractory multiple myeloma (MM) is often limited by poor marrow reserve and multi-organ impairment. In particular, renal failure occurs in up to 50% of such patients, and this further limits the use of conventional chemotherapy. Thalidomide, both alone and in combination with dexamethasone, has been demonstrated to be useful in patients with advanced MM, as responses could be achieved in 30-60% of the cases. From May 2000 to November 2003, 20 consecutive MM patients (15 males, five females, median age 66.5 yr) with stage III relapsed/refractory MM and renal failure, defined as serum creatinine >130 mmol/L, gave their informed consent to be enrolled in a clinical trial aimed at evaluating the efficacy and the toxic effects of thalidomide. Three patients were undergoing chronic haemodialysis during the time of entry in the study. Eight patients have been treated with thalidomide as a single agent, at a starting dose of 100 mg/d, that was to be increased to 400 mg/d in case of good tolerance. Twelve patients have been treated with thalidomide at the maximum dose of 200 mg/d plus dexamethasone 40 mg/d for four consecutive days every 4 wk. A >50% decrease in serum or urine M component was observed in nine patients (45%), seven of whom have been treated with thalidomide + dexamethasone and three with thalidomide alone. Six additional patients achieved a minor response (>25% paraprotein decrease); the total response rate was thus 75%. Median response duration was 7 months (range 2-24 months). Four patients were refractory to treatment. Recovery of a normal renal function was observed in 12 of 15 responsive patients, two additional patients, in chronic haemodialysis, showed a reduction of serum creatinine. Toxicity profile of thalidomide with or without dexamethasone was comparable with that observed in patients with a normal renal function. In conclusion, our data show that thalidomide can be safely administered in patients with advanced MM and renal failure.